Abstract
Listeria monocytogenes (Lm) is a saprophyte and intracellular pathogen. Transition to the pathogenic state relies on sensing of host-derived metabolites, yet it remains unclear how these are recognized and how they mediate virulence gene regulation. We previously found that low availability of isoleucine signals Lm to activate the virulent state. This response is dependent on CodY, a global regulator and isoleucine sensor. Isoleucine-bound CodY represses metabolic pathways including branched-chain amino acids (BCAA) biosynthesis, however under BCAA depletion, as occurs during infection, BCAA biosynthesis is upregulated and isoleucine-unbound CodY activates virulence genes. While isoleucine was revealed as an important input signal, it was not identified how internal levels are controlled during infection. Here we show that Lm regulates BCAA biosynthesis via CodY and via a riboregulator located upstream to the BCAA biosynthesis genes, named Rli60. rli60 is transcribed when BCAA levels drop, forming a ribosome-mediated attenuator that cis-regulates the downstream genes according to BCAA supply. Notably, we found that Rli60 restricts BCAA production, essentially starving Lm, a mechanism that is directly linked to virulence, as it controls the internal isoleucine pool and thereby CodY activity. This controlled BCAA auxotrophy likely evolved to enable isoleucine to serve as a host signal and virulence effector.
Highlights
Listeria monocytogenes (Lm) is a facultative intracellular bacterial pathogen and the causative agent of listeriosis disease [1]
Bacterial pathogens must adapt to their host environment to carry out a successful infection
We provide compelling evidence that fine tuning branched-chain amino acids (BCAA) biosynthesis in L. monocytogenes allows the bacteria to sense isoleucine as a host-specific signal
Summary
Listeria monocytogenes (Lm) is a facultative intracellular bacterial pathogen and the causative agent of listeriosis disease [1]. Lm senses the low availability of BCAA within the host cell cytosol and responds by triggering virulence gene expression [19] This response is dependent on the global transcription regulator and metabolic sensor, CodY, which directly binds isoleucine and activates or represses genes [21,22]. CodY repression of the metabolic genes is alleviated and the unbound CodY becomes an activator of PrfA and thereby the downstream virulence genes [19,20,23] While these findings placed CodY at the crossroad of metabolism and virulence, they revealed isoleucine to be a key signaling molecule within the host that influences gene expression. Considering this observation, we speculated that Lm may have evolved additional mechanisms that finely tunes BCAA biosynthesis, enabling isoleucine to serve as a host signal and effector of virulence
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